Degeneration, traumas and injuries of the nervous system, comprising brain, spinal cord and peripheral nerves, are characteristic of certain diseases and common consequences of accidents. Cerebrovascular accident (CVA) is a clinical definition used to describe symptoms of an acute neurological disorder caused by disturbance of the cerebral blood supply. Intracerebral and subarachnoid hemorrhages account for approx 20% of CVAs and 80% are of ischemic type. Stroke defines all conditions in which the duration of the CVA symptoms exceeds 24 h. Hemorrhagic strokes may be situated intra- or extracerebrally. Intracerebral hemorrhage can be caused by artery aneurysm rupture, and a subdural hemorrhage by cranial trauma. See, Ter Horst G J and Postigo A., In: Ter Horst G J and Korf J (eds.), ClinicalPharmacology of Cerebral Ischemia, Humana Press, Totowa, N.J., 1-30, 1997, the entire disclosure of which is incorporated herein by reference.
The causes of ischemic stroke are numerous and include large artery atherosclerosis, small vessel occlusion, embolisms, and thrombosis. Focal (regional) ischemia is clinically more common than global (forebrain) ischemia A focal insult usually occurs after thrombosis or embolus in the middle cerebral artery, whereas global ischemia results from transient cardiac arrest. See, Ter Horst G J and Postigo A., In: Ter Horst G J and Korf J (eds.), Clinical Pharmacology of Cerebral Ischemia, Humana Press, Totowa, N.J., 1-30, 1997.
If such damages, traumas or injuries as described above are not treated in a proper way they can lead to extensive death of nerve cells leading further to several permanent symptoms, including paralysis and other motor dysfunctions, sense disorders, mental disorders or even death of the patient.
The need to control cerebrovascular accidents and spinal cord injuries has led to a search for therapeutic agents and treatment methods that are both safe and effective. Animal studies and clinical trials have shown that amino acid transmitters (especially glutamate), oxidative stress and inflammatory reactions contribute strongly to cell death in brain diseases and damages. There are available some pharmacological methods to prevent cell deaths in the above cases. However, these methods have severe limitations and/or side-effects so that in practice there is no effective medical method for the treatment of cerebral stroke and spinal cord injuries. For example, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate, dizocilpine maleate) and CNS 1102 block another type of glutamate receptor and are neuroprotective in several rodent models of brain ischemia. See, Muir K W, Grosset D G and Lees K R (1995). Ann. NY Acad. Sci. 765:279-289; Muir K W, Lees K R (1995). Stroke 26:503-513; Kornhuber J, Weller M (1997). Biol. Psych. 41:135-144; Marshall L F, Marshall S B (1995). New Horiz. 3:573-580; Bullock R (1995). Ann. NY Acad. Sci 765:272-278; the entire disclosures of which are each incorporated herein by way of this reference. However, these compounds lead to hallucinations and cause vacuolization and death of certain cortical neurons. See Olney J W (1994). Psychopharmacol. Bull. 30:533-540, the entire disclosure of which is incorporated herein by this reference. NBQX (6-nitro-7-sulphamoylbenzo (f) quinoxaline-2,3dione (disodium)) acts as an antagonist of glutamate receptors, but it causes interstitial tubular nephrite and hallusinations. See, Muir K W, Lees K R (1995). Stroke 26:503-513;Marshall L F, Marshall S B (1995). New Horiz. 3:573-580; and Buchan A M, Lesiuk H, Bames K A, Li H, Huang Z-G, Smith K E, Xue D (1993). Stroke 24:I148-I151, Suppl. I, the entire disclosures of which are incorporated herein by way of this reference. Oxidative stress can be prevented with antioxidative enzymes, which unfortunately have very short half-life, typically only minutes or hours, in vivo. e.g. Cu,Zn-superoxidedismutase (Cu, Zn-SOD) protects cells agains oxidative stress but its half-life in vivo is, in free form, 6 min and, as conjugated, 38 hours. See Liu T H, Beckman J S, Freeman B A, Hogan E L and Hsu Y (1989). Am. J. Physiol. 256:H589-H593, the entire disclosure of which is incorporated herein by this reference. In addition, even though antioxidative compounds and anti-inflammatory drugs cross the blood-brain barrier, cerebral concentration high enough for neuronal protection is not usually achieved. See Chan P H, Longar S, Fishman R A (1987). Ann. Neurol. 21:540-547.;Insel P A: Chapter 26, 638-681 in: Goodman and Gilman (eds) the Pharmacological Basis of Therapeutics. Eight edition, Pergamon Press, New York, 1990; and Grilli M, Pizzi M, Memo M, Spano P (1996). Science 274:1383-1385; the entire disclosures of which are incorporated herein by way of this reference.
As a result, there is a significant and very long-standing need to identify new methods and/or new agents with favourable benefit to risk ratios that can be applied topically (locally) or given systemically to prevent or suppress (i.e. "treat") neuronal death after damages, traumas and diseases of the brain and spinal cord, and the associated symptoms of paralysis, cardiac complications, psychosis and agitation. Optimally, such agents should be effective when administered topically (locally) or systemically and systemic absorption should not result in blood levels high enough to cause significant systemic toxicity or other adverse side effects.
It is therefore an object of the present invention to provide methods for treating brain stroke (brain ischemias and hemorrhages) and spinal cord injuries.
It is another object of the present invention to provide methods for systemic treatment of brain stroke (brain ischemias and hemorrhages) and spinal cord injuries.
It is yet another object of the present invention to provide methods for topical/local treatment of brain ischemias (brain stroke) and spinal cord injuries.